A major hurdle for the development of drug formulations is the hydrophobic nature of many therapeutic compounds, which hampers the solubility and bioavailability of a drug. To overcome this limitation, numerous new drug formulations are explored, such as liposomes, micelles and emulsions.
Examples of such lipophilic therapeutic compounds are macrolides, such as cyclosporine (e.g. cyclosporine A (CsA)), rapamycin/sirolimus (RAP or SIR) and FK506/tacrolimus (TAC), or the like, such as everolimus, ridaforolimus, temsirolimus, umirolimus, zotarolimus, ascomycin, FK1012 or pimecrolimus, or structurally related compounds, or palmitoylethanolamide (PEA).
CsA is an immunosuppressant agent widely used in organ transplantation to prevent rejection. It reduces the activity of the immune system by interfering with the activity and growth of T-cells. In particular, CsA binds to the cytosolic protein cyclophilin (immunophilin) present in lymphocytes, especially T-cells. This complex of cyclosporin and cyclophilin subsequently inhibits calcineurin, which is responsible for activating the transcription of interleukin 2 and related cytokines. Cyclosporine also inhibits lymphokine production and interleukin release and, therefore, reduces the function of effector T-cells.
The first oral CsA formulation introduced into clinical use (Sandimmune) comprised a solution of CsA dissolved in a solvent system of olive oil and ethanol (Patentschrift (Switz.) CH 641 356, Feb. 29, 1984, Appl. 79/1949. Feb. 27, 1979). The oil was emulsified in water using a polyethoxylated oleic glyceride surfactant to give a coarse O/W emulsion. This system was found to be inherently thermodynamically unstable. As a result, the drug tended to precipitate out of solution, and thus not be absorbed.
As described for CsA above, similar thermodynamically unstable solutions, leading to drug precipitation are known to occur for other macrolides, such as rapamycin/sirolimus and FK506/tacrolimus, or the like, such as everolimus, ridaforolimus, temsirolimus, umirolimus, zotarolimus, ascomycin, FK1012 or pimecrolimus, or structurally related compounds.
Solvent-free formulations with relatively high concentrations of rapamycin and ridaforolimus using micelles with PEG-phospholipid conjugates (such as DSPE-PEG2000) have been described in the art (Remsberg et al., Pharmaceutics 2013, 5, 81-93; Vakil et al., Pharm. Res. 2008, 25, 2056-2064), as well as for a large range of other lipophilic drugs such as palmitoylethanolamide (PEA), miconazole, paclitaxel, docetaxel, nelfinavir mesylate, propofol, diazepam and ixabepilone. However, all these formulations were found to be thermodynamically unstable, both at storage conditions and (once diluted below the critical micelle concentration) in biological fluids. In fact, Remsberg et al. (supra) described that: “For unclear reasons, solubilization of ridaforolimus in DSPE-PEG2000 micelles did not dramatically increase the residence time or the overall systemic exposure of ridaforolimus. This may be indicative of a lack of in vivo stability or an inability to evade the mononuclear phagocyte system.” In addition, Vakil et al. (supra) demonstrated that the micellar rapamycin formulation: “however, had no significant effect of the pharmacokinetic disposition of rapamycin with only a longer tv1/2 being significant.” These results are in accordance with the results found in the Remsberg at al. (supra) study. There clearly is a need in the art for a stable formulation for immunomodulatory macrolides, e.g. in biological fluids, as well as under storage conditions.
The lipophilic agent PEA is a fatty acid amide that occurs naturally in humans, and belongs to the class of nuclear factor agonists. PEA has been demonstrated to bind to a nuclear receptor and exerts a great variety of biological functions related to chronic pain and inflammation. Currently, the only available form of this lipophilic drug is micronized, ultramicronized or a cyclodextrin-entrapped form. For example, the ultramicronized form of palmitoylethanolamide, gives rise to high plasma levels of a metabolite of palmitoylethanolamide, 2-arachidonoylglycerol (2-AG), which is known to be less effective than PEA for the treatment of chronic pain and inflammation.
Delivery of lipophilic drugs such as macrolides (e.g. CsA and/or SIR and/or TAC) and/or PEA to the eye is especially challenging, due to the unique protective mechanisms of the eye. In particular, there are three barriers to ocular penetration: The corneal epithelium, the blood-aqueous barrier and the blood-retinal barriers.
The common routes of drug administration for the treatment of eye disorders are topical, systemic, periocular and intravitreal. Topical administration is the most preferred route because of the highest patient compliance and the least invasive nature. Upon topical administration, absorption of a drug takes place either through the corneal route (cornea, aqueous humor, intraocular tissues) or noncorneal route (conjunctiva, sclera, choroid/retinal pigment epithelium (RPE)). Only a small fraction of the topically applied drugs, generally less than 5%, reaches the intraocular tissues (Mishra G P et al. J. of Drug Delivery (2011) 2011:863734). Factors responsible for poor ocular bioavailability following topical instillation are precorneal drainage and the lipoidal nature of the corneal epithelium. In addition, a major fraction of the drug reaches the systemic circulation through conjunctival vessels and the nasolacrimal duct, which can lead to severe adverse effects. Hence, the topical route has only been successful to a limited extent so far.
Systemic administration requires the administration of high doses due to the blood-aqueous barrier and blood-retinal barrier. Such high doses can lead to severe side effects. Furthermore, intravitreal administration requires frequent administration, which may cause susceptibility for vitreous haemorrhage, retinal detachment and endophthalmitis. Thus there is a clear need to improve the delivery of drugs to the eye.
The lipophilic drug cyclosporine A (CsA) has been explored for dry eye syndrome, autoimmune uveitis and the prevention of corneal graft rejection. CsA has also been investigated for treating several eye infections, such as posterior blepharitis, atopic keratoconjunctivitis and herpetic stromal keratitis (DiTommaso et al. Invest Ophthalmol. Vis. Sci. (2012) 53(4):2292-9). For many of these diseases, high systemic concentrations of CsA have to be administered to reach therapeutic ocular drug levels, resulting in serious side effects, such as nephrotoxicity and hypertension. Hence, a topical and local CsA administration would be favourable.
Restasis (Allergen, Irvin, Calif.) is an ophthalmic emulsion comprising CsA for dry eye treatment. Restasis is a white opaque to slightly translucent homogeneous emulsion comprising 0.05% CsA. The CsA is formulated in a polyoxyethylene castor oil (Cremophor EL).
Cremophor EL is responsible for a painful burning or stinging sensation after application of eye drops, as well as for e.g. infusion reactions after intravenous applications. These side effects caused by Cremophor EL limit the dosing amount and frequency. Furthermore, the low formulation strength and rapid clearance from the eye or body requires continued dosing to be effective, further leading to poor patient compliance. Cremophor is a commonly used emulsifier for lipophilic drugs. For example, the drugs miconazole, paclitaxel, docetaxel, nelfinavir mesylate, propofol, diazepam, vitamin K and ixabepilone are usually formulated in a polyoxyethylene castor oil (Cremophor EL).
Cyclokat and Vekacia are two other ophthalmic emulsions, which are based on a cationic technology called Novasorb (Novagali Pharma, France). The concentration CsA in these emulsions is 0.1% (Lallemand et al. J. Of Drug Delivery (2012): 2012:604204). The formulation CyclASol (Novaliq) is based on Semi-Fluorinated Alkanes (SFAs) and comprises 0.05% CsA.
Yet, other formulations containing a higher concentration of CsA comprise a lipid or fat milky (IntraLipid) emulsion of 5 mg/mL CsA (0.5%). Such emulsions are ready to be used intravenously and are currently explored for cardiac and brain disorders (CicloMulsion® and NeuroSTAT®). Locally used formulations are however prepared in dimethyl sulfoxide (DMSO), which is also quite toxic to cells and tissues.
The lipophilic agent PEA is currently used in eye drops in veterinary medicine for its soothing activity (Oculvet Drops). In addition, a clinical study has demonstrated that oral administration of PEA was effective in reducing the increased intraocular pressure (TOP) after the iridotomy procedure. In another clinical trial, PEA was found to significantly reduce IOP in patients diagnosed with primary open-angle glaucoma (POAG) or with ocular hypertension and it seems that PEA increases aqueous humor outflow through the trabecular meshwork (TM) pathway (Kumar et al).
Besides the delivery of diagnostic or therapeutic lipophilic agents to the eye, eye drops may also be used for the treatment of dry and irritated eyes. In such case, the eye drop formulation does not need to comprise an active lipophilic agent, but comprises ingredients to lubricate and soothe the irritated eye. Such eye drop formulations are commonly known as artificial tears. Notably, there is currently no stable artificial tear formulation available in the art that is clear, comprises naturally occurring soothing lipids and is also moisturizing to the eye.
There is thus still a need in the art for improved (stable, inert, clear and solvent-free) formulations of lipophilic agents (such as immunomodulatory macrolides) for the systemic or topical administration of an effective concentration of such agents. In particular, there is a need in the art for such formulations for the treatment or alleviation of a skin, mucosal or eye disease or disorder, without causing (severe) side effects at the site of administration.